OBJECTIVE: The aim of this study was to determine the developmental risk pathway to depression by 16 years in offspring of postnatally depressed mothers. METHOD: This was a prospective longitudinal study of offspring of postnatally depressed and nondepressed mothers; child and family assessments were made from infancy to 16 years. A total of 702 mothers were screened, and probable cases interviewed. In all, 58 depressed mothers (95% of identified cases) and 42 nondepressed controls were recruited. A total of 93% were assessed through to 16-year follow-up. The main study outcome was offspring lifetime clinical depression (major depression episode and dysthymia) by 16 years, assessed via interview at 8, 13, and 16 years. It was analysed in relation to postnatal depression, repeated measures of child vulnerability (insecure infant attachment and lower childhood resilience), and family adversity. RESULTS: Children of index mothers were more likely than controls to experience depression by 16 years (41.5% versus 12.5%; odds ratio = 4.99; 95% confidence interval = 1.68-14.70). Lower childhood resilience predicted adolescent depression, and insecure infant attachment influenced adolescent depression via lower resilience (model R(2) = 31%). Family adversity added further to offspring risk (expanded model R(2) = 43%). CONCLUSIONS: Offspring of postnatally depressed mothers are at increased risk for depression by 16 years of age. This may be partially explained by within child vulnerability established in infancy and the early years, and by exposure to family adversity. Routine screening for postnatal depression, and parenting support for postnatally depressed mothers, might reduce offspring developmental risks for clinical depression in childhood and adolescence.